PKMYT1 inhibitors (Iktos)

PKMYT1 is a crucial regulator of the cell cycle, particularly involved in the G2/M transition through the inhibitory phosphorylation of CDK1, and is a promising therapeutic target for cancer therapy. Data mining in the Roche kinome screen database identified a hit characterized by 100% PKMYT1 inhibitory activity at a 10 μM concentration, which was further validated with a PKMYT1 enzymatic assay showing double-digit nanomolar potency. The hit featured a quinolinone central core and a phenol headgroup. The replacement of the problematic phenol headgroup with an indazole moiety induced a flip in the kinase hinge cysteine and glycine residues, resulting in a series of derivatives with enhanced potency, superior kinome selectivity, and no GSH flag. Further structural fine-tuning led to the discovery of compound 36, a novel, selective, and potent PKMYT1 inhibitor with favorable oral pharmacokinetic profiles and promising in vivo antitumor efficacy.

The protein kinase PKMYT1 is responsible for inhibitory CDK1 phosphorylation, thus playing a central role in regulating the G2/M cell cycle checkpoint. As many cancers have dysfunctional cell cycle checkpoint signaling, PKMYT1 inhibition is emerging as an attractive target in advanced tumors. PKMYT1 inhibitors, however, have encountered difficulties in balancing biological efficacy, on-target specificity, and favorable stability and other drug-like properties. Herein, we report the design and development of pyrrolopyrimidinone derivatives intended to simultaneously restrict molecular conformation and shield a metabolic site in order to optimize stability. Compound 7 demonstrated strong PKMYT1-specific inhibition, a subsequent decrease in CDK1 phosphorylation, and antitumor efficacy in vitro, as well as enhanced metabolic stability, favorable pharmacokinetic and bioavailability properties, and potent antitumor in vivo efficacy. Our findings indicate that compound 7 is a promising PKMYT1 inhibitor for the treatment of advanced cancers with cell cycle defects.